Low-temperature plasma patch for enhancing transdermal delivery of useful substances and transdermal delivery method using same

Abstract

The present application provides a low-temperature plasma patch for enhancing transdermal delivery of useful substances and a transdermal delivery method using same. More specifically, the present application provides a low-temperature plasma patch for enhancing transdermal delivery of useful substances and a transdermal delivery method using same, wherein the patch can be attached to the skin to temporarily weaken the skin barrier and facilitate the delivery of useful substances such as transdermal drugs.

Description

Low-temperature plasma patch for enhancing delivery of useful substances via transdermal penetration and transdermal delivery method using the same

[0001] The present invention relates to a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration and a transdermal delivery method using the same. More specifically, the present invention relates to a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration that can be attached to the skin to temporarily weaken the skin barrier, thereby facilitating the delivery of useful substances such as transdermal drugs, and a method for delivering useful substances through the skin using the same.

[0002] Transdermal drug delivery technology can deliver drugs that are difficult to deliver orally through the skin, and has the advantage of increasing drug penetration and promoting blood absorption compared to application to the skin surface, allowing for faster action and self-administration.

[0003] In particular, in the case of drugs used to treat skin diseases, such as steroids, skin penetration is difficult, which can lead to side effects (skin infection, skin atrophy, pigmentation, allergic reactions, etc.) due to overuse. To mitigate this, transdermal drug delivery technology is required to efficiently deliver small amounts of medication. Such technologies are diverse and rapidly developing.

[0004] Microneedles (patches) are invasive devices used to deliver drugs through the dermis or transdermis. While this microneedle (patch) technology offers the advantages of precise drug delivery to the target site and less pain than injections, there is a risk of side effects. These include microneedles breaking and remaining within the skin upon removal, as well as erythema, itching, or infection.

[0005] Iontophoresis is a non-invasive method of drug delivery using electrical stimulation. The aforementioned iontophoresis technology has the advantage of being able to control the speed and amount of drug delivery by regulating electrical stimulation. However, the technology has the disadvantage that there may be electrical stimulation, and drug selection is limited as it is effective only against ionized drugs.

[0006] Sonophoresis is a non-invasive method that uses ultrasonic energy to deliver drugs through the skin, and unlike iontophoresis, it allows for the application of a wide variety of drugs. However, ultrasound is effective only near the skin surface, resulting in low efficiency, and it has the disadvantage of high maintenance costs for the ultrasound equipment.

[0007] As background technology of the present invention, Korean published patent No. 10-2023-0099191 describes an electrode-type biodegradable metal microneedle patch for enhancing drug delivery.

[0008] The purpose of this invention is to provide a low-temperature plasma patch capable of enhancing the delivery of useful substances, such as transdermal drugs, through a non-invasive method.

[0009] Another objective of the present invention is to provide a low-temperature plasma patch for enhancing transdermal drug delivery that can induce a synergistic effect with drugs for skin diseases.

[0010] Another objective of the present invention is to provide a transdermal delivery method for useful substances that can enhance the delivery of useful substances, such as transdermal drugs, using a low-temperature plasma patch in a non-invasive manner.

[0011] Another objective of this institute is to provide a transdermal drug delivery method capable of inducing a synergistic effect with drugs for treating skin diseases.

[0012] Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims, and drawings.

[0013] According to one aspect, a low-temperature plasma patch for enhancing the delivery of useful substances through transdermal penetration is provided, comprising: a low-temperature plasma generator; an adhesive member provided on one side of the low-temperature plasma generator to attach the low-temperature plasma generator to a target; and a spacer provided on the other side of the low-temperature plasma generator to separate the low-temperature plasma generator from the target at a certain distance, and promoting the delivery of useful substances through transdermal penetration to improve or treat dermatitis of a target.

[0014] According to one embodiment, the low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration of the present invention can control the delivery of useful substances through the dermis by controlling the plasma generated from the low-temperature plasma generator to cause changes in the stratum corneum of the skin and rearrangement of the intercellular lipid layer.

[0015] According to one embodiment, the useful substance of the present invention may be one or more of dexamethasone, clobetasol, desonide, and methylprednisolone.

[0016] According to one embodiment, the low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration of the present invention can induce the treatment of dermatitis and antibacterial action by drugs with one or more of the active oxygen species and nitrogen species generated from the low-temperature plasma generator.

[0017] According to one embodiment, in a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to the present invention, the low-temperature plasma generating device comprises a dielectric layer; a first electrode formed on one side of the dielectric layer; and a second electrode formed on the other side of the dielectric layer, wherein at least one of the first electrode and the second electrode may be arranged in a certain pattern.

[0018] According to one embodiment, in the low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration of the present invention, the low-temperature plasma generator may be a low-temperature atmospheric pressure plasma generator operated by a low-frequency power source.

[0019] According to one embodiment, the inner side of the adhesive member of the low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration of the present invention may be provided with a mounting portion on which the low-temperature plasma generating device is mounted.

[0020] According to one embodiment, the low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration of the present invention can reduce the thickness of one of the epidermis and dermis of the skin of a subject with dermatitis.

[0021]

[0022] According to another aspect, a method for transdermal delivery of a useful substance is provided, comprising the step of delivering a useful substance through the dermis of a target using a low-temperature plasma patch for enhancing transdermal delivery of a useful substance according to the present invention.

[0023] According to one embodiment, the method for transdermal delivery of a useful substance according to the present invention can control the delivery of a useful substance through the dermis by controlling the plasma generated from the low-temperature plasma generator to change the stratum corneum of the skin and rearrange the intercellular lipid layer.

[0024] According to one embodiment, in the method for transdermal delivery of a useful substance according to the present invention, the useful substance may be a substance for improving dermatitis.

[0025] According to one embodiment, in the method for transdermal delivery of a useful substance according to the present invention, the substance for improving dermatitis may be one or more of dexamethasone, clobetasol, desonide, and methylprednisolone.

[0026] According to one embodiment, in the method for transdermal delivery of a useful substance according to the present invention, the target may be a mammal other than a human.

[0027] According to one embodiment, in the method for transdermal delivery of a useful substance according to the present invention, the useful substance may be a cosmetic for skin improvement.

[0028]

[0029] According to another aspect, a method is provided to reduce the expression of one or more of total immunoglobulin E, DFE (Dermatophagoides farinae extract) specific immunoglobulin, IL-4, and IL-13 in subjects with dermatitis by using a low-temperature plasma patch for enhancing transdermal delivery of useful substances.

[0030]

[0031] According to one embodiment of the present invention, the low-temperature plasma patch of the present invention can improve the delivery of useful substances, such as drugs, by temporarily weakening the skin barrier through changes in the stratum corneum of the skin and rearrangement of intercellular lipids.

[0032] According to one embodiment of the present invention, the low-temperature plasma patch of the present invention can temporarily weaken the skin barrier as described above, thereby enhancing the delivery of useful substances, such as drugs that are difficult to penetrate the skin or drugs, through the skin to sensitive areas. Therefore, effective treatment may be possible even when administering a lower dose of drugs compared to conventional methods, and side effects caused by overdose administration of steroids, antibiotics, etc., may be prevented.

[0033] According to one embodiment of the present invention, the low-temperature plasma patch of the present invention can improve skin health by temporarily weakening the skin barrier as described above to promote the absorption of functional ingredients such as anti-aging ingredients, skin regeneration ingredients, wrinkle improvement ingredients, whitening ingredients, and moisturizing ingredients.

[0034] According to one embodiment of the present invention, the low-temperature plasma patch of the present invention can optimize the delivery of useful substances via transdermal penetration by controlling plasma generation conditions.

[0035] According to one embodiment of the present invention, the low-temperature plasma patch of the present invention can induce a synergistic effect with a skin disease treatment drug by generating oxygen-nitrogen active species, thereby providing antibacterial effects and preventing infection.

[0036] According to one embodiment of the present invention, the transdermal drug delivery method of the present invention can enhance transdermal drug delivery by using a low-temperature plasma patch and reduce inflammation caused by infection, thereby significantly improving intractable skin diseases such as dermatitis when used in combination with drugs.

[0037]

[0038] FIG. 1a is a schematic plan view of a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to one embodiment of the present invention.

[0039] FIG. 1b is a schematic cross-sectional view of a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to one embodiment of the present invention.

[0040] Figure 2 is a photograph showing the state of a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to one embodiment of the present invention before discharge (Figure 2 (a)) and during discharge (Figure 2 (b)).

[0041] FIG. 3 is a schematic cross-sectional view showing the state in which a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to one embodiment of the present invention is attached after applying a drug to the skin.

[0042] FIG. 4 is a QV Lissajous diagram showing the discharge power consumption according to the driving conditions of a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to one embodiment of the present invention.

[0043] Figure 5 is a graph showing the results of measuring ozone concentration according to the operating conditions of a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to one embodiment of the present invention.

[0044] FIG. 6 is a schematic diagram showing an animal experiment plan according to one embodiment of the present invention.

[0045] Figure 7 is a photograph confirming the effect of improving atopic dermatitis in the dorsal tissue of a mouse with induced atopic dermatitis by applying a low-temperature plasma patch according to one embodiment of the present invention.

[0046] Figure 8 is a graph showing the change in dorsal skin thickness of mice in each experimental group during an animal experiment according to one embodiment of the present invention.

[0047] FIG. 9(a) is an image showing the change in thickness of the dorsal epidermis and dermis and the degree of eosinophil infiltration of mice in each experimental group during an animal experiment according to one embodiment of the present invention, using hematoxylin and eosin staining. FIG. 9(b) is an image showing the degree of mast cell infiltration of mice in each experimental group during an animal experiment according to one embodiment of the present invention, using toluidine blue staining.

[0048] FIG. 10 is a graph showing the total immunoglobulin E expression amount, immunoglobulin G2a expression amount, and DFE-specific immunoglobulin E expression amount measured in the serum of mice of each experimental group during an animal experiment according to one embodiment of the present invention.

[0049] FIGS. 11 and 12 are graphs showing the relative expression levels of inflammatory cytokine mRNA released from dorsal tissue samples of experimental group mice and human keratinocyte cell lines (HaCaT cells) that induce and exacerbate atopic dermatitis during animal experiments according to one embodiment of the present invention, in Th1, Th2, and Th17 cells. FIG. 11 shows the relative expression levels of IL-4, IL-13, IL-6, IL-17A, TNF-α, IL-1β, IFN-γ, and CCL-17, and FIG. 12 shows the relative expression levels of IL-1β, IL-6, CCL-17, and CCL-22.

[0050] Figure 13 is an image confirming the skin barrier repair effect in the dorsal tissue of a mouse with induced atopic dermatitis when a low-temperature plasma patch according to one embodiment of the present invention is applied, based on the expression levels of Occludin, Claudin-1, and ZO-1 tight junction proteins and Masson's trichrome.

[0051] FIG. 14 is an image showing the degree of penetration of a drug into the epidermal and dermal layers of the skin when a low-temperature plasma patch is applied according to one embodiment of the present invention.

[0052] Figure 15 is an image showing the results of a fluorescent staining experiment performed in vitro on a human keratinocyte cell line (HaCaT cell) to confirm whether the application of a low-temperature plasma patch according to one embodiment of the present invention helps in the intracellular absorption of a drug.

[0053] FIG. 16 is an image showing the results of histological analysis of the kidney and liver to confirm side effects on animal experiment mice when a low-temperature plasma patch according to one embodiment of the present invention is applied.

[0054] FIG. 17 is a graph showing the results of measuring the body weight (Fig. 17 (a)) and organ weight (Fig. 17 (b)) of a mouse when a low-temperature plasma patch according to one embodiment of the present invention is applied.

[0055] FIG. 18a is a photograph showing the synergistic therapeutic effect on atopic dermatitis when a low-temperature plasma patch according to one embodiment of the present invention is combined with clobetasol, desonide, and methylprednisolone, respectively.

[0056] FIG. 18b is a graph showing the change in dorsal skin thickness of an animal experiment mouse when a low-temperature plasma patch according to one embodiment of the present invention is combined with clobetasol, desonide, and methylprednisolone, respectively.

[0057] The above-mentioned objectives, means, and resulting effects of the present invention will become clearer through the following detailed description in conjunction with the attached drawings, and accordingly, a person skilled in the art to which the present invention pertains will be able to easily implement the technical concept of the present invention. Furthermore, in describing the present invention, if it is determined that a detailed description of known technology related to the present invention may unnecessarily obscure the essence of the present invention, such detailed description will be omitted.

[0058] The terms used herein are for describing the embodiments and are not intended to limit the invention. In this specification, the singular form includes the plural form as appropriate unless specifically stated otherwise in the text. In this specification, terms such as “comprising,” “providing,” “arranging,” or “having” do not exclude the presence or addition of one or more other components in addition to the components mentioned.

[0059] In this specification, terms such as "or", "at least one," etc., may represent one of the words listed together or a combination of two or more. For example, "or B", "at least one of and B" may include only one of A or B, or may include both A and B.

[0060] In this specification, descriptions following "e.g." should not limit the embodiments of the invention according to the various embodiments thereof, such as variations including tolerances, measurement errors, limits of measurement accuracy, and other commonly known factors, as the information presented, such as cited characteristics, variables, or values, may not exactly match.

[0061] In this specification, where it is stated that a component is 'connected' or 'connected' to another component, it should be understood that it may be directly connected or connected to the other component, or that there may be other components in between. On the other hand, when it is mentioned that a component is 'directly connected' or 'directly connected' to another component, it should be understood that there are no other components in between.

[0062] In this specification, where a component is described as being 'on' or 'in contact' with another component, it should be understood that it may be in direct contact with or connected to the other component, but that another component may exist in between. Conversely, where a component is described as being 'immediately above' or 'in direct contact' with another component, it should be understood that no other component exists in between. Other expressions describing the relationship between components, such as 'between' and 'directly between,' may be interpreted in the same way.

[0063] In this specification, terms such as 'first', 'second', etc., may be used to describe various components, but such components should not be limited by the said terms. Furthermore, the said terms should not be interpreted as limiting the order of each component, but may be used for the purpose of distinguishing one component from another. For example, 'first component' may be named 'second component', and similarly, 'second component' may be named 'first component'.

[0064] Unless otherwise defined, all terms used in this specification may be used in a meaning commonly understood by those skilled in the art to which this invention pertains. Additionally, terms defined in commonly used dictionaries are not to be interpreted ideally or excessively unless explicitly and specifically defined otherwise.

[0065] Microorganisms in this institution include bacteria, fungi, viruses, etc.

[0066] In this context, prevention refers to anything that suppresses or delays the symptoms of various skin conditions, including atopic dermatitis.

[0067] In this context, improvement refers to at least reducing parameters related to the treated condition of various dermatitis, including atopic dermatitis, such as the severity of symptoms.

[0068] At this clinic, treatment refers to reversing or alleviating the symptoms of various dermatitis, including atopic dermatitis, or inhibiting or preventing their progression.

[0069]

[0070] FIG. 1a is a schematic plan view of a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to one embodiment of the present invention. FIG. 1b is a schematic cross-sectional view of a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration according to one embodiment of the present invention.

[0071] Referring to FIG. 1a and FIG. 1b, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration according to the present invention comprises: a low-temperature plasma generator (10); an adhesive member (20) provided on one side of the low-temperature plasma generator (10) to attach the low-temperature plasma generator (10) to a target; and a spacer (30) provided on the other side of the low-temperature plasma generator (10) to separate the low-temperature plasma generator and the target at a certain distance.

[0072]

[0073] FIG. 2 is a photograph showing the state of a low-temperature plasma patch for enhancing transdermal delivery of useful substances according to one embodiment of the present invention before discharge (Fig. 2 (a)) and during discharge (Fig. 2 (b)). FIG. 3 is a schematic cross-sectional view showing the state of a low-temperature plasma patch for enhancing transdermal delivery of useful substances according to one embodiment of the present invention attached after applying a drug to the skin.

[0074] Referring to FIGS. 2 and 3, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention controls the plasma (P) generated during the discharge of the low-temperature plasma generator (10) to induce changes in the stratum corneum of the skin and the rearrangement of the intercellular lipid layer, thereby temporarily weakening the skin barrier (S) and enhancing the delivery of useful substances, such as drugs (D), via transdermal penetration. As described above, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention can temporarily weaken the skin barrier to enhance the delivery of useful substances, such as drugs, via transdermal penetration to sensitive areas or drugs that are difficult to penetrate through the skin. Consequently, effective treatment may be possible even with a lower dose of drugs than conventional methods, and side effects caused by the overdose administration of steroids, antibiotics, etc., may be prevented. In particular, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention can improve or treat atopic dermatitis in subjects by promoting the transdermal penetration of drugs useful for atopic dermatitis, which is an intractable disease requiring continuous management. Furthermore, by controlling the amount of plasma generated by the plasma generator (10), the useful substances can be delivered and absorbed in a customized manner according to the needs of the subjects being treated.

[0075] Although not limited thereto, the above useful substances in this invention may be one or more of dexamethasone, clobetasol, desonide, and methylprednisolone. As described above, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration in this invention can control the plasma (P) generated from the low-temperature plasma generator (10) to induce changes in the stratum corneum of the skin and rearrangement of the intercellular lipid layer, thereby temporarily weakening the skin barrier and promoting the transdermal penetration of dexamethasone, clobetasol, desonide, or methylprednisolone, which are treatments for skin conditions such as atopic dermatitis. Therefore, equivalent efficacy can be achieved with a smaller amount, thereby minimizing side effects caused by excessive application (skin infection, skin atrophy, pigmentation, allergic reaction, etc.).

[0076] In this clinic, dermatitis may include dermatitis of various causes. Although not limited thereto, dermatitis in this clinic may include allergic dermatitis and contact dermatitis, and in particular, atopic dermatitis.

[0077] Although not limited thereto, the above-mentioned useful substance in this invention may be a cosmetic product containing functional ingredients such as anti-aging ingredients, skin regeneration ingredients, wrinkle improvement ingredients, whitening ingredients, and moisturizing ingredients. The low-temperature plasma patch of this invention can improve skin health by temporarily weakening the skin barrier as described above, thereby promoting the absorption of functional ingredients contained in cosmetics, such as anti-aging ingredients, skin regeneration ingredients, wrinkle improvement ingredients, whitening ingredients, and moisturizing ingredients.

[0078]

[0079] Although not limited thereto, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention can induce dermatitis treatment and antibacterial action by drugs with one or more of the active oxygen species and nitrogen species generated during the discharge of the low-temperature plasma generator (10). The low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention can induce synergistic effects with drugs for treating skin diseases by generating oxygen-nitrogen active species through the plasma (P) generated during discharge, thereby providing antibacterial effects and preventing infection. In particular, in the case of dermatitis, itching is accompanied, and scratching the skin to relieve the itching can easily cause wounds, and problems such as secondary infection may occur through the resulting wounds. However, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention can not only enhance the transdermal penetration of drugs but also suppress secondary infection or the induction of itching through the inactivation of microorganisms such as bacteria, fungi, and viruses present in the wound area and antibacterial activity.

[0080]

[0081] Although not limited to this, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention can reduce the thickness of either the epidermis or the dermis of the skin of a subject with dermatitis. In particular, when dermatitis such as atopic dermatitis is induced, the thickness of the epidermis and dermis of the skin increases, which can make it more difficult for drugs to penetrate the skin. However, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention can induce changes in the stratum corneum and rearrangement of the intercellular lipid layer to temporarily weaken the skin barrier, thereby enhancing the penetration of a treatment for dermatitis such as atopic dermatitis into the skin, and further enhance the penetration of a treatment for dermatitis such as atopic dermatitis by reducing the thickness of the epidermis and / or dermis. In addition, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention does not affect the thickness of the epidermis and dermis of normal skin that is not induced with dermatitis. That is, the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention has no side effects on normal cells.

[0082]

[0083] Referring to FIG. 1a and FIG. 2. Although not limited thereto, in the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention, the low-temperature plasma generator (10) may be composed of a plasma generation module (14) formed in various patterns, such as a hexagonal honeycomb pattern, inside a frame (12).

[0084] The above plasma generation module (14) can be connected with free patterning without being restricted to a specific direction and can be easily formed inside the frame (12) using a repeating pattern such as a circle, triangle, square, hexagon, octagon, or star shape using conventional known technology. Although not limited thereto, the repeating pattern can be formed by an etching method using a mask pattern similar to a known method of manufacturing a PCB substrate.

[0085] The above frame (12) can vary in shape, size, and thickness according to the needs of the application field, and the above frame (12) can be modularized to optimize it to a desired size, such as small or large, as needed, thereby providing a modular, large-sized, or portable low-temperature plasma generator (10).

[0086] The above frame (12) may be a frame equipped with an electrical connection terminal (16) connected to a control unit including a power source.

[0087] Although not limited thereto, the plasma generation module (14) of the present invention may be suitable for delivering useful substances and enhancing antimicrobial effects when operated with power consumption per unit area of ​​0.1 to 1 mW / mm², and may be more suitable when operated with power consumption per unit area of ​​0.2 to 1 mW / mm².

[0088]

[0089] Although not limited thereto, in the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention, the plasma generation module (14) of the low-temperature plasma generation device (10) comprises a dielectric layer; a first electrode formed on one side of the dielectric layer; and a second electrode formed on the other side of the dielectric layer, and at least one of the first electrode and the second electrode may be arranged in a certain pattern.

[0090] The first electrode and the second electrode may both be voltage application electrodes, and the first electrode may be a ground electrode and the second electrode may be a voltage application electrode. That is, the first electrode and the second electrode may both be connected to a power source, or each may be connected to a power source and a ground source, respectively.

[0091] Although not limited thereto, the first electrode may be a ground electrode and the second electrode may be a voltage application electrode.

[0092] The present invention is characterized by at least one of the first electrode and the second electrode being arranged in a certain pattern, although not limited thereto. That is, only one of the first electrode and the second electrode may be patterned, or both the first electrode and the second electrode may be patterned. By the above configuration, the contact surface can be maximized when treating skin disease or wound sites. Although not limited thereto, the case where the first electrode is a patterned ground electrode and the second electrode is a flat voltage application electrode may be advantageous in terms of inducing a synergistic antimicrobial effect and manufacturing productivity.

[0093] Although not limited thereto, the above dielectric may be a flexible dielectric and may be selected from the group consisting of polymers, flexible glass, fabrics, and paper.

[0094] Although not limited thereto, the above polymer may be selected from the group consisting of polyimide (PI), polyethylene terephthalate (PET), polycarbonate (PC), polyethylene (PE), polyurethane (PU), polymethyl methacrylate (PMMA), polystyrene (PS), Teflon (Polytetrafluoroethylene, PTFE), and mixtures thereof. Although not limited thereto, the above polymer may be polyimide, which is suitable in terms of strength, processability, and insulation properties.

[0095] The above dielectric is configured to insulate the voltage-applying electrode. Although not limited thereto, it is composed of an insulating film surrounding the lower surface and side of the voltage-applying electrode and an insulating film formed on the upper surface of the voltage-applying electrode, so as to surround the voltage-applying electrode, it can prevent arcing between the voltage-applying electrode and the ground electrode.

[0096] Although not limited thereto, the first electrode and the second electrode may be made of gold, silver, titanium, cobalt, chromium, copper, aluminum, stainless steel, or an alloy thereof, and when used in contact with the human body, biocompatible metals such as gold, silver, titanium, cobalt, and chromium may be more suitable.

[0097] Although not limited to this, the patterned ground electrode of the plasma generation module (14) can be configured to come into contact with the skin of the target to enhance the transdermal penetration of useful substances and maximize the antimicrobial effect.

[0098]

[0099] Although not limited to this, in the low-temperature plasma generator (10) of the present invention, a surface dielectric barrier discharge (SDBD) may be most suitable for using a large-area discharge in the form of an electric discharge. Using the surface dielectric barrier discharge has the advantage of obtaining a high concentration of active species per unit volume of the discharge area within a controllable range.

[0100]

[0101] Although not limited thereto, the plasma in the present invention may be a low-temperature atmospheric pressure plasma operated by a low-frequency power source. According to the above configuration, it is safe even when applied to the human body, and the reliability, safety, and durability of the low-temperature plasma generator (10) can be improved through dielectric protection.

[0102] Although not limited thereto, the frequency applied to the low-temperature plasma generator (10) may be 60 Hz to 35 kHz, which is suitable for efficient generation of atmospheric surface dielectric barrier discharge, prevention of excessive heat generation, and dielectric protection, and may be 1 to 35 kHz more suitable, 5 to 35 kHz more suitable, and 10 to 30 kHz more suitable. If the frequency is less than 60 Hz, it is complicated to generate power and there is insufficient atmospheric surface dielectric barrier discharge, so the enhancement of transdermal penetration of useful substances and antimicrobial effects may be insufficient, and if it exceeds 35 kHz, heat generation is severe, and internal components such as dielectrics may be destroyed.

[0103] Although not limited thereto, the voltage applied to the low-temperature plasma generator (10) may be suitable for dielectric protection and antimicrobial effects at a voltage of 1 to 5 kV, and may be more suitable at a voltage of 2 to 5 kV.

[0104] Although not limited thereto, the low-temperature plasma generator (10) can generate numerous substances such as OH radicals, oxygen anions, hydrogen peroxide, electrons, and ultraviolet rays through the plasma (P in FIG. 3) generated on both sides of the patterned first electrode. Although not limited thereto, when using dielectric barrier discharge for large-area application, OH radicals and ozone can induce enhanced transdermal penetration of useful substances and sterilization or inactivation effects on microorganisms. Additionally, volatile organic compounds (VOCs), such as aldehydes, ketones, ammonia, hydrogen sulfide, and nitrogen compounds, can also be directly decomposed through the plasma. In particular, the low-temperature plasma generator (10) can generate large amounts of ozone and hydroxyl active species, which are oxygen active species that inactivate viruses.

[0105]

[0106] Referring to FIG. 1b, although not limited thereto, a mounting portion (20a, 20b) on which the low-temperature plasma generator (10) is mounted may be provided on the inner side of the adhesive member (20) of the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention.

[0107] The shape and structure of the above-mentioned seating portions (20a, 20b) can be formed in various ways using known technology, and in the present invention, the above-mentioned seating portions (20a, 20b) are, for example, grooves formed by protrusions extending from the inner side of the adhesive member (20) toward the center so that the end of the low-temperature plasma generator (10) is fitted therein.

[0108]

[0109] The spacer (30) of the present invention is configured to secure a discharge space for the low-temperature plasma generator (10) of the present invention to improve discharge efficiency and to protect the skin of the subject. Accordingly, it is suitable for the spacer (30) to be provided while maintaining a certain distance from the low-temperature plasma generator (10). As long as it can perform the above function, the spacer (30) has no special limitations and can be composed of known materials. Although not limited thereto, it may be suitable for the spacer to be composed of porous materials such as sterile gauze or sponge so that oxygen-nitrogen active species generated by the plasma discharged by the low-temperature plasma generator (10) of the present invention can pass through, and for hygiene and safety.

[0110]

[0111] Referring to FIGS. 2 and FIGS. 3, a method for transdermal delivery of a useful substance according to another aspect of the present invention includes the step of delivering a useful substance through the skin of a target using a low-temperature plasma patch for enhancing transdermal delivery of a useful substance according to the present invention.

[0112] Although not limited to this, the delivery of useful substances through the dermis can be controlled by controlling the plasma generated from the above-mentioned low-temperature plasma generator through changes in the stratum corneum of the skin and the rearrangement of the intercellular lipid layer.

[0113] As described above, by using the low-temperature plasma patch (1) for enhancing the delivery of useful substances via transdermal penetration of the present invention, the plasma (P) generated during the discharge of the low-temperature plasma generator (10) can be controlled to induce changes in the stratum corneum of the skin and the rearrangement of the intercellular lipid layer, thereby temporarily weakening the skin barrier (S) and enhancing the delivery of useful substances, such as drugs (D), through the skin. Furthermore, by controlling the amount of plasma generated by the plasma generator (10), the useful substances can be delivered and absorbed in a customized manner according to the needs of the subject being treated.

[0114] Although not limited thereto, in the method of transdermal delivery of useful substances according to the present invention, the useful substance may be a substance for improving dermatitis. By using the low-temperature plasma patch (1) for enhancing transdermal delivery of useful substances according to the present invention, the transdermal penetration of a drug useful for dermatitis, such as atopic dermatitis which requires continuous management as an intractable disease, can be promoted to improve or treat the subject's atopic dermatitis.

[0115] Although not limited thereto, in the method for transdermal delivery of useful substances according to the present invention, the substance for improving dermatitis may be one or more of dexamethasone, clobetasol, desonide, and methylprednisolone. As described above, the low-temperature plasma patch (1) for enhancing transdermal delivery of useful substances according to the present invention controls the plasma (P) generated from the low-temperature plasma generator (10) to induce changes in the stratum corneum of the skin and rearrangement of the intercellular lipid layer, thereby temporarily weakening the skin barrier and promoting the transdermal penetration of dexamethasone, clobetasol, desonide, or methylprednisolone, which are substances for improving and / or treating dermatitis such as atopic dermatitis. Therefore, equivalent efficacy can be achieved with a smaller amount, thereby minimizing side effects caused by excessive application (skin infection, skin atrophy, pigmentation, allergic reaction, etc.).

[0116] Although not limited thereto, in the method for transdermal delivery of useful substances according to the present invention, the subject may be a mammal other than a human.

[0117] Although not limited thereto, in the method for transdermal delivery of useful substances according to the present invention, the useful substance may be a cosmetic product containing functional ingredients such as anti-aging ingredients, skin regeneration ingredients, wrinkle improvement ingredients, whitening ingredients, and moisturizing ingredients. The low-temperature plasma patch according to the present invention can improve skin health by temporarily weakening the skin barrier as described above, thereby promoting the absorption of functional ingredients contained in the cosmetic product, such as anti-aging ingredients, skin regeneration ingredients, wrinkle improvement ingredients, whitening ingredients, and moisturizing ingredients.

[0118]

[0119] According to another aspect, the present invention provides a method for reducing the expression of one or more of total immunoglobulin E, DFE-specific immunoglobulin, IL-4, and IL-13 in subjects with induced dermatitis by using the present invention’s low-temperature plasma patch for enhancing transdermal delivery of useful substances.

[0120] Although not limited to this, the expression of immunoglobulins, genes, etc., associated with various inflammations can be controlled using the low-temperature plasma patch of the present invention for enhancing the delivery of useful substances via transdermal penetration. In particular, the expression of one or more of total immunoglobulin E, DFE-specific immunoglobulin, IL-4, and IL-13 associated with dermatitis such as atopic dermatitis can be reduced.

[0121] Total immunoglobulin E (IgE) is an immunoglobulin composed of glycoproteins with a molecular weight of approximately 200,000. It is detected in serum, nasal discharge, sputum, and serous fluid and is an immunoglobulin involved in allergic reactions. It increases systemically or locally in the presence of allergies, but according to the present invention, its expression can be reduced.

[0122] DFE-specific immunoglobulin is an immunoglobulin that is specifically expressed in house dust mite extracts, and according to the present invention, its expression can be reduced.

[0123] IL-4 and IL-13 are cytokines associated with atopic dermatitis, asthma, chronic rhinosinusitis, and allergic rhinitis, and according to the present invention, the expression of IL-4 and IL-13 can be simultaneously reduced.

[0124]

[0125] Hereinafter, a preferred embodiment according to the present invention will be described in detail with reference to the attached drawings.

[0126]

[0127] Examples

[0128] Experimental Example 1. Analysis of discharge power consumption according to operating conditions of the low-temperature plasma patch of the present invention

[0129] The discharge power consumption was verified according to the operating conditions of the low-temperature plasma patch of the present invention. At this time, to simulate the environment of attachment to actual skin, pig skin was placed under the low-temperature plasma patch, and the power consumption was measured according to the following operating conditions 1 and 2.

[0130] 1) Power of Driving Condition 1 (Condition_1): 0.136 mW / mm²

[0131] 2) Power of Driving Condition 2 (Condition_2): 0.242 mW / mm²

[0132] The results are shown in Fig. 4. Fig. 4 is a QV Lissajous diagram showing the discharge power consumption according to the driving conditions of a low-temperature plasma patch for enhancing transdermal drug delivery according to one embodiment of the present invention. As shown in Fig. 4, the discharge power consumption was greater in driving condition 2 than in driving condition 1.

[0133]

[0134] Experimental Example 2. Analysis of changes in ozone concentration according to the operating conditions of the low-temperature plasma patch of the present invention

[0135] Changes in ozone concentration according to the operating conditions of the low-temperature plasma patch of the present invention were analyzed. Changes in ozone concentration according to the following operating conditions 1 and 2 were measured.

[0136] 1) Power of Driving Condition 1 (Condition_1): 0.136 mW / mm²

[0137] 2) Power of Driving Condition 2 (Condition_2): 0.242 mW / mm²

[0138] At this time, ozone concentration was measured using Optical Absorption Spectroscopy (OAS). In addition, to simulate the situation of actual skin application, pig skin was placed under the plasma patch, and measurements were conducted inside an ozone measurement chamber with a volume of 246 cm³ that was isolated from the outside air.

[0139] The results are shown in Fig. 5. Fig. 5 is a graph showing the results of measuring ozone concentration according to the operating conditions of a low-temperature plasma patch for enhancing transdermal drug delivery according to one embodiment of the present invention. As shown in Fig. 5, the ozone concentration increased in operating condition 2 compared to operating condition 1, and the ozone concentration was maintained at a constant level for a long time.

[0140]

[0141] Experimental Example 3. Inhibitory effect of the present invention's low-temperature plasma patch on atopic dermatitis

[0142] Experimental Example 3-1. Animal Care

[0143] Seven-week-old female BALB / c mice were purchased from the Hyochang Laboratory Animal Center, and four mice were housed per cage in a dedicated space maintained at a temperature of 22 ± 2 ℃, a relative humidity of 55 ± 5%, and a 12-hour light-dark cycle. The care and treatment provided to the mice followed the guidelines set forth in the Public Health Service Policy on the Humane Care and Use of Laboratory Animals and were approved by the Kyungpook National University Animal Care and Use Committee (KNU-2023-0283).

[0144] Experimental Example 3-2. Preparation of an Atopic Dermatitis Animal Model and Application of the Low-Temperature Plasma Patch of the Present Institution

[0145] To confirm the efficacy of the present invention's low-temperature plasma patch on mice with atopic dermatitis, an atopic dermatitis mouse model was constructed. Specifically, 7-week-old female BALB / c mice were used, and house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) were used to induce atopic dermatitis. After removing the dorsal hair of the mice, DFE (10 mg / ml) and 1% DNCB were applied to each mouse for 2 weeks. After confirming the induction of atopic dermatitis, dexamethasone (Dexa) and / or the present invention's low-temperature plasma patch were applied and continued for 2 weeks (see Fig. 6). Dexamethasone (Dexa) was used as a positive control.

[0146] The experimental group was divided as follows.

[0147] 1: Negative control group (normal group):

[0148] 2: Atopic dermatitis-inducing group: AD

[0149] 3: Atopic dermatitis induction + Dexa group: AD+Dexa

[0150] 4: Induction of atopic dermatitis + Application of our clinic's low-temperature plasma patch Group: AD+CAP

[0151] 5: Atopic dermatitis induction + Dexa + Application of our clinic's low-temperature plasma patch Group: AD+Dexa+CAP

[0152] The effect of the low-temperature plasma patch of our institute on mice with atopic dermatitis was confirmed visually (see Fig. 7), and dorsal thickness was measured once a week using a dial thickness gauge (Mitutyo, Co., Tokyo, Japan) (see Fig. 8). On the last day of the experiment, the mice were euthanized with CO2, and samples were collected for additional experiments.

[0153]

[0154] Figure 7 is a photograph showing the visual confirmation of the effect of improving atopic dermatitis in the dorsal tissue of mice with induced atopic dermatitis by applying a low-temperature plasma patch according to one embodiment of the present invention. As shown in Figure 7, it was confirmed that atopic dermatitis was improved more in the experimental group treated with the low-temperature plasma patch of the present invention and in the experimental group treated with dexamethasone and the low-temperature plasma patch of the present invention in combination than in the experimental group treated with dexamethasone, a representative treatment for atopic dermatitis. In particular, it was confirmed that atopic dermatitis was significantly improved in the experimental group treated with dexamethasone and the low-temperature plasma patch of the present invention in combination.

[0155] Figure 8 is a graph showing the change in dorsal skin thickness of mice in each experimental group during an animal experiment according to one embodiment of the present invention. As shown in Figure 8, it was confirmed that the skin thickness decreased more in the experimental group treated with dexamethasone, a representative treatment for atopic dermatitis, and the experimental group treated with the low-temperature plasma patch of the present invention, compared to the experimental group treated with dexamethasone and the experimental group treated with the low-temperature plasma patch of the present invention. It was confirmed that the skin thickness decreased significantly in the experimental group treated with dexamethasone and the low-temperature plasma patch of the present invention, and furthermore, after 3 weeks, the skin thickness reduction effect was significantly different compared to other experimental groups.

[0156] Experimental Example 3-3. Confirmation of clinical symptoms in an atopic dermatitis model by application of the present invention's low-temperature plasma patch

[0157] To confirm the clinical symptoms of an atopic dermatitis model resulting from the application of the low-temperature plasma patch of the present invention, skin tissues of animal models in the experimental group were fixed with 10% formaldehyde, stained with hematoxylin, eosin, and toluidine blue, and observed under a microscope.

[0158] The results are shown in FIG. 9. Specifically, FIG. 9(a) is an image showing the change in thickness of the dorsal epidermis and dermis and the degree of eosinophil infiltration of mice in each experimental group during an animal experiment according to one embodiment of the present invention, using hematoxylin and eosin staining. FIG. 9(b) is an image showing the degree of mast cell infiltration of mice in each experimental group during an animal experiment according to one embodiment of the present invention, using toluidine blue staining.

[0159] As shown in Figure 9(a), it was confirmed that the epidermal and dermal thickness and the degree of eosinophil infiltration (reduction in eosinophil penetration) were reduced more in the experimental group treated with the low-temperature plasma patch of the present invention and in the experimental group treated with dexamethasone and the low-temperature plasma patch of the present invention than in the experimental group treated with dexamethasone, a representative treatment for atopic dermatitis. In particular, it was confirmed that in the experimental group treated with dexamethasone and the low-temperature plasma patch of the present invention, the epidermal and dermal thickness were similar to that of the normal group, which is the negative control, and the degree of eosinophil infiltration was significantly reduced.

[0160] In addition, as shown in Fig. 9(b), it was confirmed that the degree of mast cell infiltration was reduced more significantly in the experimental group treated with the low-temperature plasma patch of the present invention and in the experimental group treated with dexamethasone and the low-temperature plasma patch of the present invention compared to the experimental group treated with dexamethasone, a representative treatment for atopic dermatitis. In particular, it was confirmed that the degree of mast cell infiltration was significantly reduced in the experimental group treated with dexamethasone and the low-temperature plasma patch of the present invention.

[0161] Experimental Example 3-4. Confirmation of the inhibitory effect on serum immunoglobulin E and immunoglobulin G2a expression in an atopic dermatitis model by the application of the present invention's low-temperature plasma patch

[0162] After the 4-week experiment of the animal model prepared in Experimental Example 3-2, the mice were sacrificed and blood was collected. The serum was separated by centrifugation at 3,000 rpm for 15 minutes, and the levels of immunoglobulin E and immunoglobulin G2a were measured using BD Biosciences' ELISA kit.

[0163] Specifically, capture antibodies (Anti-mouse IgE, anti-mouse IgG2a) were each diluted 1:250 in coating buffer (8.40g NaHCO3, 3.56g Na2CO3 in 1L distilled water, pH 9.5), 100µl was dispensed into each well, and the mixture was reacted at 4°C for 24 hours, followed by washing 3 times with wash buffer (0.05% Tween-20 PBS). Next, 200µl of assay diluent (10% FBS in PBS) was dispensed into each well, the mixture was reacted at room temperature for 1 hour, and the mixture was washed 5 times with wash buffer. Next, mouse serum was diluted to 1:100-1000 in the assay diluent, 100 µl was dispensed into each well, and the mixture was reacted at room temperature for 2 hours and washed 5 times. Then, detection antibodies (Biotin rat-anti mouse IgE, Bioninylated-anti-mouse IgG2a) and enzyme reagent (SAv-HRP) were each diluted to 1:250 in the assay diluent, 100 µl was added to each well, and the mixture was reacted at room temperature for 1 hour, followed by 5 washes for 1 minute each. Finally, 100 µl of substrate solution was dispensed, the area was shielded from light for 30 minutes, 50 µl of stop solution was added, and the absorbance was measured at 450 nm using an ELISA reader.

[0164] The results are shown in FIG. 10. Specifically, FIG. 10 is a graph showing the total immunoglobulin E expression, immunoglobulin G2a expression, and DFE-specific immunoglobulin E expression measured in the serum of mice of each experimental group during an animal experiment according to one embodiment of the present invention. As shown in FIG. 10, compared to the group treated with dexamethasone alone, it was confirmed that the experimental groups treated with the low-temperature plasma patch of the present invention or with the low-temperature plasma patch of the present invention together with dexamethasone reduced the levels of serum immunoglobulin E (total IgE and DFE-specific IgE) and immunoglobulin G2a, which show increased expression in atopic dermatitis, to an equivalent or significantly lower level ( FIG. 10).

[0165] Experimental Example 3-5. Confirmation of the inhibitory effect of the present invention's low-temperature plasma patch on the expression of inflammatory cytokines in an atopic dermatitis model

[0166] The inhibitory effect of the low-temperature plasma patch of the present invention on the expression of inflammatory cytokines that increase in atopic dermatitis was confirmed. Specifically, after the completion of a 4-week experiment in the animal model prepared in Experimental Example 3-2, mice were sacrificed and dorsal skin tissue was obtained, and the expression of inflammatory cytokines in the dorsal skin tissue was measured. Cells were obtained by treating with Trizol solution, and then centrifuged with the addition of chloroform. RNA was isolated by centrifugation with the addition of isopropanol.

[0167] cDNA was synthesized using Maxime RT PreMix (Random primer, iNtRON Biotechnology), and 2 µl of cDNA, 1 µl of sense and antisense primer solution (GenoTech Corp) (see Table 1), SYBR Green PCR Master Mix (Applied Biosystems), and dH2O were mixed together per tube to make a total of 20 µl. After performing qPCR on the expression of IL-4, IL-13, IL-6, IL-17A, TNF-α, IL-1β, IFN-γ, and CCL-17 mRNA, the results were analyzed using TP850 software.

[0168]

[0169]

[0170] The results are shown in Fig. 11. Specifically, Fig. 11 is a graph showing the relative expression levels of inflammatory cytokine mRNA released from Th1, Th2, and Th17 cells that induce and exacerbate atopic dermatitis in dorsal tissue samples of experimental group mice during an animal experiment according to one embodiment of the present invention, wherein the inflammatory cytokines are IL-4, IL-13, IL-6, IL-17A, TNF-α, IL-1, IFN-γ, and CCL-17. As shown in Fig. 11, it was confirmed that the experimental group to which the low-temperature plasma patch of the present invention was applied together with dexamethasone reduced the expression levels of most inflammatory cytokines, which show increased expression in atopic dermatitis, to a significantly lower level, i.e., to the level of the negative control (normal group), compared to the group to which dexamethasone was applied alone (Fig. 11).

[0171] Experimental Example 3-6. Confirmation of the inhibitory effect of the present invention's low-temperature plasma patch on the expression of inflammatory cytokines in human keratinocytes

[0172] We confirmed the inhibitory effect of our low-temperature plasma patch on the expression of inflammatory cytokines in human keratinocytes. To this end, 2×10 5Keratinocytes were pretreated with dexamethasone (2 μM) and the low-temperature plasma patch of the present invention for 1 hour, and then stimulated with TNF-α and IFN-γ (10 ng / ml) for 6 hours.

[0173] Chloroform was added to the above keratinocytes and centrifuged. RNA was isolated by centrifugation with the addition of isopropanol.

[0174] cDNA was synthesized using Maxime RT PreMix (Random primer, iNtRON Biotechnology), and 2 µl of cDNA, 1 µl of sense and antisense primer solution (GenoTech Corp) (see Table 2), SYBR Green PCR Master Mix (Applied Biosystems), and dH2O were mixed together per tube to make a total of 20 µl. After performing qPCR on the expression of IL-1β, IL-6, CCL-17, and CCL-22 mRNA, the results were analyzed using TP850 software.

[0175]

[0176] The results are shown in Fig. 12. Specifically, Fig. 12 is a graph showing the relative expression levels of inflammatory cytokine mRNA released from Th1, Th2, and Th17 cells that induce and exacerbate atopic dermatitis in human keratinocyte cell lines (HaCaT cells) according to one embodiment of the present invention, wherein the cytokines are IL-1, IL-6, CCL-17, and CCL-22. As shown in Fig. 12, it was confirmed that the experimental group to which the low-temperature plasma patch of the present invention was applied, or to which the low-temperature plasma patch of the present invention was applied together with dexamethasone, reduced the expression of inflammatory cytokines in human keratinocytes to a lower level compared to the group to which dexamethasone was applied alone, or to a level equivalent to or significantly lower than that of the negative control (normal group) (Fig. 12).

[0177] Experimental Example 3-7. Confirmation of overexpression of tight-linked genes in the low-temperature plasma patch of the present invention

[0178] Tight junctions regulate epidermal permeability to control the passage of water, ions, and solutes, and protect the human body from harmful external influences. Recent studies have shown that dexamethasone induces the overexpression of tight junction genes. To determine whether the application of the low-temperature plasma patch at our institute affects tight junction protein levels, immunohistochemical staining was first performed using samples derived from in vivo experiments.

[0179] Specifically, dorsal skin tissue fixed with 10% formaldehyde was deparaffinized with xylene, followed by rehydration using ethanol. After non-specific binding blockade, the respective primary and secondary antibodies were used. The primary antibodies Occludin (abcam), Cluadin1 (invitrogen), and ZO-1 (abcam) were stained in appropriate ratios, respectively, and the process was finished with the Vector ABC-HRP system. In the same manner, the primary and secondary antibodies were used in human keratinocyte cell lines (HaCaT cells) after fixation and non-specific binding blockade.

[0180] The results of the above immunohistochemical analysis are shown in Fig. 13. Specifically, Fig. 13 is an image confirming the skin barrier repair effect in the dorsal tissue of a mouse with induced atopic dermatitis (Fig. 13(a)) and human keratinocyte cell line (HaCaT cell) (Fig. 13(b)) upon application of a low-temperature plasma patch according to one embodiment of the present invention, based on the expression levels of Occludin, Cluadin-1, and ZO-1 tight junction proteins and Masson's trichrome. As shown in Fig. 13, it was confirmed that the experimental group to which the low-temperature plasma patch of the present invention was applied, or the group to which the low-temperature plasma patch of the present invention was applied together with dexamethasone, reduced the expression of tight junction protein cytokines to a lower level compared to the group to which dexamethasone was applied alone, or to a level equivalent to or significantly lower than that of the negative control (normal group).

[0181]

[0182] Experimental Example 4. Confirmation of the efficacy of transdermal drug penetration using the low-temperature plasma patch of the present invention

[0183] We investigated how the application of the present invention's low-temperature plasma patch affects skin permeability. The stratum corneum of the skin acts as an effective barrier that blocks the penetration of most external substances. Additionally, it is known that in patients with atopic dermatitis, skin absorption of drugs decreases when the skin thickens. To determine whether the application of the present invention's low-temperature plasma patch affected drug penetration in patients with atopic dermatitis, dexamethasone (2 mg / ml) conjugated with a fluorescent substance and / or the present invention's low-temperature plasma patch were applied to mice with induced atopic dermatitis.

[0184] The results are shown in Fig. 14. That is, Fig. 14 is an image showing the degree of penetration of a drug into the epidermal and dermal layers of the skin when a low-temperature plasma patch is applied, in order to confirm whether the application of a low-temperature plasma patch according to one embodiment of the present invention helps in the intracellular absorption of the drug.

[0185] FIG. 15 is an image showing the fluorescence staining results of an in vitro experiment performed on a human keratinocyte cell line (HaCaT cell) to confirm whether the application of a low-temperature plasma patch according to one embodiment of the present invention aids in the intracellular absorption of a drug. For this purpose, 5×10 5 After treating keratinocytes with dexamethasone (100 μM) conjugated with a fluorescent substance and / or the low-temperature plasma patch of the present invention, the penetration of the drug into the cells was confirmed after 1 hour, 3 hours, 6 hours, and 12 hours. Images were analyzed at a magnification of 400x using a Carl Zeiss microscope. As shown in Figures 14 and 15, it was confirmed that the experimental group in which dexamethasone was applied in combination with the low-temperature plasma patch of the present invention significantly enhanced the intracellular absorption of the drug compared to the experimental group in which dexamethasone was applied alone.

[0186]

[0187] Experimental Example 5. Confirmation of side effects of the present invention's low-temperature plasma patch

[0188] The application of the present invention's low-temperature plasma patch (CAP) did not cause changes in serological or immunological factors in animal experiment mice. To determine whether the application of the CAP had harmful effects on the body, the present invention's low-temperature plasma patch was applied to the dorsal skin of normal mice and mice with induced atopic dermatitis for 12 consecutive days. When the present invention's low-temperature plasma patch was applied, it was carried out for 5 to 10 minutes under conditions of 2.96 kV, 3.52 kV, and 4.16 kV.

[0189] The results are shown in FIGS. 16 and 17. Specifically, FIG. 16 is a figure showing the results of histological analysis of the kidney and liver to confirm side effects in experimental mice when a low-temperature plasma patch according to one embodiment of the present invention is applied. In addition, FIG. 17 is a graph showing the results of measuring the body weight (Fig. 17 (a)) and organ weight (Fig. 17 (b)) of mice when a low-temperature plasma patch according to one embodiment of the present invention is applied. As shown in FIGS. 16 and 17, it was found that there were no side effects in experimental mice even when the low-temperature plasma patch of the present invention was applied.

[0190]

[0191] Experimental Example 6. Confirmation of synergistic effect of combined application of the present invention's low-temperature plasma patch and therapeutic agent

[0192] The following experiment was conducted to confirm the synergistic effect when our low-temperature plasma patch is applied in combination with various treatments for dermatitis, including atopic dermatitis.

[0193] Experimental Example 6-1. Animal Care

[0194] Seven-week-old female BALB / c mice (n=24) purchased from the Korean Center for Laboratory Animals (Daegu, South Korea) were used. Mice were housed at a density of three per cage in a dedicated space maintained at a temperature of 22±2°C, a relative humidity of 55±5%, and a 12-hour light-dark cycle throughout the study. The care and treatment provided to the mice followed the guidelines set forth in the Public Health Service Policy on the Humane Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Kyungpook National University.

[0195] Experimental Example 6-2. Preparation of an animal model for atopic dermatitis and the combined effect of the present invention's low-temperature plasma patch and therapeutic agent

[0196] To confirm the synergistic effect of our low-temperature plasma patch on mice with atopic dermatitis, an atopic dermatitis mouse model was constructed. Specifically, 7-week-old female BALB / c mice were used, and house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) were used to induce atopic dermatitis.

[0197] DFE (Prolagen, Seoul, South Korea) was dissolved in 1x phosphate-buffered saline containing 0.5% Tween 20. 1% 2,4-dinitrochlorobenzene (DNCB) (Sigma-Aldrich, St. Louis, Missouri, USA) was dissolved in acetone / olive oil at a ratio of 1:3. The steroid drugs clobetasol propionate (Clobetasol), desonide, and methylprednisolone were purchased in Cayman, Michigan, and dissolved in saline with 5% DMSO.

[0198] All drugs were administered at a dose of 12.5 μg / kg. The dorsal skin surface was removed using a depilatory cream. After hair removal, a total of 50 μL of DFE (1 mg / mL), 1% DNCB, or 0.5% DNCB was applied to each mouse, excluding the negative control group. After confirming the induction of atopic dermatitis, one of clobetasol propionate (clobetasol), desonide, and methylprednisolone and / or the present invention's low-temperature plasma patch (2.96 kV, 5 min) were applied and continued for 2 weeks. Dorsal skin thickness was measured once a week using a dial thickness gauge (Mitutoyo, Co., Tokyo, Japan). On the last day of the experiment, mice were euthanized with CO2, and samples were collected for further experiments.

[0199] The experimental group was divided into 8 groups as follows.

[0200] 1: Negative control group (normal group):

[0201] 2: Atopic dermatitis-inducing group: AD

[0202] 3: Atopic dermatitis induction + Clobetasol Group: AD+Clobetasol

[0203] 4: Atopic dermatitis induction + Clobetasol group + Group with our clinic's low-temperature plasma patch applied: AD+Clobetasol+CAP

[0204] 5: Induces atopic dermatitis + Desonide group: AD+Desonide

[0205] 6: Atopic dermatitis induction + Desonide group + Group with our clinic's low-temperature plasma patch applied: AD+Desonide+CAP

[0206] 7: Induces atopic dermatitis + Methylprednisolone Group: AD+Methylprednisolone

[0207] 8: Atopic dermatitis induction + Methylprednisolone group + Group with application of our clinic's low-temperature plasma patch: AD+Methylprednisolone+CAP

[0208]

[0209] As described above, a DNCB / DFE-induced AD model was used to examine the effects of the present invention's low-temperature plasma patch on general steroids. Atopic dermatitis was induced for two weeks, and its severity was assessed based on the following symptoms, including erythema, edema, and scarring. To compare morphological changes in the skin, photographs were taken on the last day of the experiment, and the results are shown in Fig. 18a. Specifically, Fig. 18a is a photograph showing the synergistic therapeutic effect on atopic dermatitis when the low-temperature plasma patch according to one embodiment of the present invention is applied in combination with one of Clobetasol, Desonide, and Methylprednisolone. As shown in Fig. 18a, when the present invention's low-temperature plasma patch was applied after steroid treatment, skin lesions were significantly reduced for all three drugs; in particular, when Desonide and Methylprednisolone were applied in combination, skin lesions were almost completely reduced, indicating a remarkably superior therapeutic effect for atopic dermatitis.

[0210] In addition, the thickness of the back skin was measured once a week during the experiment period, and the results are shown in FIG. 18b. That is, FIG. 18b is a graph showing the change in the thickness of the back skin of an animal experiment mouse when a low-temperature plasma patch according to one embodiment of the present invention is combined with one of clobetasol, desonide, and methylprednisolone.

[0211] The effect of the low-temperature plasma patch of our institute was confirmed one week after application. In addition, it was confirmed that the dorsal skin thickness of mice with induced atopic dermatitis was significantly reduced when combined with the low-temperature plasma patch of our institute compared to the application of a steroid drug alone.

[0212] These results demonstrate that the low-temperature plasma patch of our institute is highly effective in enhancing the delivery and therapeutic effects of topical steroid drugs in atopic dermatitis.

[0213]

[0214] Although specific embodiments have been described in the detailed description of this application, it is understood that various modifications are possible without departing from the scope of this application. Therefore, the scope of this application is not limited to the described embodiments but should be defined by the claims set forth below and equivalents thereof.

[0215]

[0216] [Explanation of the symbol]

[0217] 1: Low-temperature plasma patch

[0218] 10: Low-temperature plasma generator

[0219] 12: Frame

[0220] 14: Plasma generation module

[0221] 16: Terminal section

[0222] 20: Adhesive member

[0223] 20a, 20b: Seating parts

[0224] 30: Spacer

Claims

1. Low-temperature plasma generator; An adhesive member provided on one surface of the above-mentioned low-temperature plasma generator for attaching the low-temperature plasma generator to a target body; and A spacer provided on the other side of the above-mentioned low-temperature plasma generator to separate the low-temperature plasma generator and the target object at a certain distance; A low-temperature plasma patch for enhancing transdermal delivery of useful substances, which improves or treats dermatitis in a subject by promoting transdermal delivery of useful substances.

2. In Paragraph 1, A low-temperature plasma patch for enhancing transdermal delivery of useful substances, which controls the plasma generated from the above-mentioned low-temperature plasma generator to regulate the delivery of useful substances through the dermis by changing the stratum corneum of the skin and rearranging the intercellular lipid layer.

3. In Paragraph 1, A low-temperature plasma patch for enhancing transdermal delivery of useful substances, wherein the useful substance is one or more of dexamethasone, clobetasol, desonide, and methylprednisolone.

4. In Paragraph 1, A low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration, which induces the treatment of dermatitis and antibacterial action by one or more of active oxygen species and nitrogen species generated from the above-mentioned low-temperature plasma generator and a drug.

5. In Paragraph 1, The above-mentioned low-temperature plasma generator is Genome layer; A first electrode formed on one side of the dielectric layer; and It includes a second electrode formed on the other side of the above dielectric layer, and A low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration, wherein at least one of the first electrode and the second electrode is arranged in a certain pattern.

6. In Paragraph 1, The above-mentioned low-temperature plasma generator is a low-temperature atmospheric pressure plasma generator operated by a low-frequency power source, a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration.

7. In Paragraph 1, A low-temperature plasma patch for enhancing transdermal drug delivery, wherein a mounting portion for mounting the low-temperature plasma generator is provided on the inner side of the adhesive member.

8. In Paragraph 1, A low-temperature plasma patch for enhancing transdermal delivery of useful substances, which reduces the thickness of either the epidermis or the dermis of the skin in which dermatitis has been induced in the subject.

9. A method for transdermal delivery of a useful substance, comprising the step of delivering the useful substance through the skin of a target using a low-temperature plasma patch for enhancing transdermal delivery of the useful substance described in claim 1.

10. In Paragraph 9, A method for transdermal delivery of useful substances, wherein the plasma generated from the above-mentioned low-temperature plasma generator controls the delivery of useful substances through the dermis by changing the stratum corneum of the skin and rearranging the intercellular lipid layer.

11. A method for transdermal delivery of a useful substance, wherein the useful substance is a substance for improving dermatitis, in accordance with claim 9.

12. A method for transdermal delivery of a useful substance according to claim 11, wherein the substance for improving dermatitis is one or more of dexamethasone, clobetasol, desonide, and methylprednisolone.

13. A method for transdermal delivery of a useful substance, wherein the subject is a mammal excluding humans, in accordance with paragraph 12.

14. A method for transdermal delivery of a useful substance, wherein the useful substance is a cosmetic for skin improvement in claim 9.

15. A method for reducing the expression of one or more of total immunoglobulin E, DFE (Dermatophagoides farinae extract) specific immunoglobulin, IL-4, and IL-13 in a subject with induced dermatitis using a low-temperature plasma patch for enhancing the delivery of useful substances via transdermal penetration described in claim 1.

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